Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
  • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/06—Antianaemics
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
  • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
  • C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical

Definitions

• Imidazolylcyanoguanidines in which the imidazole and cyanoguanidine are joined through a linear connecting group are known as H-2 receptor inhibitors. See U.S. Pat. No. 3,950,333 to Durant et al. In addition, compounds have been prepared similar to those of Durant et al in which the imidazole moiety has been replaced by an alkylaminoalkylfuran moiety. See U.S. Pat. No. 4,128,658 to Price et al. The instant compounds differ in utilizing the aminoalkyl benzofuran moiety.
• This invention is concerned with aminoalkyl benzofuran compounds wherein the aminoalkyl benzofuran is connected to a guanidine or guanidine-like moiety through a linear connecting group.
• a further object of this invention is to descrbe processes for the preparation of such compounds.
• a still further object is to describe the use of such compounds as gastric acid secretion inhibitors in mammals. Further objects will become apparent from a reading of the following description.
• R 1 and R 2 are independently loweralkyl of from 1-3 carbons and R 1 and R 2 may be joined to form together with the nitrogen atom to which they are attached, a 5- or 6-membered heterocyclic ring, which may optionally contain another hetero atom selected from oxygen or N-R 4 wherein R 4 is hydrogen or loweralkyl;
• X is sulfur or a methylene group
• n 2,3 or 4;
• R 3 is hydrogen loweralkyl, cycloloweralkyl, cycloloweralkylloweralkyl, loweralkenyl, loweralkynyl, phenylloweralkyl, hydroxyloweralkyl, loweralkoxyloweralkyl and di(loweralkyl)aminoloweralkyl;
• Y is sulfur, ⁇ CHNO 2 or ⁇ NR 4
• R 4 is nitro, cyano or loweralkylsulfonyl.
• loweralkyl unless otherwise defined is intended to include those alkyl groups, of either a straight or branched configuration, which contain from 1-5 carbon atoms. Exemplary of such alkyl groups are methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, pentyl and the like.
• loweralkoxy is intended to include those alkoxy groups of either straight or branched configuration, which contain from 1-5 carbon atoms. Exemplary of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy and the like.
• loweralkenyl is intended to include those alkenyl groups, of either a straight or branched configuration, which contain from 2-5 carbon atoms.
• alkenyl groups are vinyl, allyl, butenyl, 1-methyl-2-butenyl, pentenyl, and the like.
• loweralkynyl is intended to include those alkynyl groups of either straight or branched configuration which contain from 2-5 carbon atoms. Exemplary of such alkynyl groups are ethynyl, propargyl, butynyl, pentynyl and the like.
• the heterocycle formed when R 1 and R 2 are joined may be piperidine, or pyrrolidine and the like.
• cycloloweralkyl is intended to include those cycloalkyl groups which contain from 3-6 carbon atoms. Exemplary of such groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
• the heterocycle formed by joining R 1 and R 2 may be piperidine, pyrrolidine, morpholine, piperazine, N-methyl piperazine and the like.
• R 1 and R 2 are the same and are loweralkyl of from 1-3 carbon atoms;
• X is sulfur
• n 2;
• R 3 is hydrogen, loweralkyl or loweralkynyl
• Y is ⁇ CHNO 2 , or ⁇ N--CN
• R 1 and R 2 are methyl
• X is sulfur
• n 2;
• R 3 is hydrogen, methyl, ethyl, or propargyl
• Y is ⁇ CH--NO 2 or ⁇ N--CN.
• R 1 and R 2 are methyl
• X is sulfur
• n 2;
• R 3 is hydrogen or methyl
• Y is ⁇ CH--NO 2 or ⁇ N--CN.
• the compounds according to the invention readily form physiologically acceptable salts.
• Such salts include salts with inorganic and organic acids such as hydrochlorides, hydrobromides and sulphates.
• Particularly useful salts of organic acids are formed with aliphatic mono- or di-carboxylic acids. Examples of such salts are acetates, maleates and fumarates.
• the compounds may also form hydrates.
• the compounds according to the invention can be administered orally, topically or parenterally or by suppository, of which the preferred route is the oral route. They may be used in the form of the base or as a physiologically acceptable salt. They will be in general be associated with a pharmaceutically acceptable carrier or diluent, to provide a pharmaceutical composition.
• the compounds according to the invention can be administered in combination with other active ingredients, e.g. conventional antihistamines if required.
• active ingredients e.g. conventional antihistamines
• the pharmaceutical composition can most conveniently be in the form of capsules or tablets, which may be slow release tablets.
• the composition may also take the form of a dragee or may be in syrup form.
• Suitable topical preparation include ointments, lotions, creams, powders and sprays.
• a convenient daily dose by the oral route would be of the order of 100 mg. to 1.2 g. per day, in the form of dosage units containing from 20 to 200 mg. per dosage unit.
• a convenient regimen in the case of a slow release tablet would be twice or three times a day.
• Parenteral administration may be by injection at intervals or as a continuous infusion. Injection solutions may contain from 10 to 100 mg./ml. of active ingredient.
• compositions may contain an effective amount of the active ingredient, for example of the order of 11/2 to 2% by weight of the total composition.
• the compounds of the present invention may be made by reacting a primary amine of the formula: ##STR2## in which R 1 , R 2 , n, and X have the meanings given herein with a compound capable of introducing directly or indirectly the group: ##STR3## in which R 3 and Y have the meanings given herein.
• Compounds which are capable of directly introducing the group: ##STR4## are, isothiocyanates R 3 NCS, or compounds of the formula: ##STR5## wherein P is a leaving group.
• the reaction with the isothiocyanate may be carried out by allowing the amine and isothiocyanate to stand in a solvent such as acetonitrile.
• the reaction between the amine (II) and: ##STR6## may be carried out in a solvent e.g. ethanol or acetonitrile at ambient or elevated temperatures in the presence of silver nitrate as required.
• the amine (II) and the compound. ##STR7## may be stirred in solvents such as ethanol and acetonitrile at ambient or elevated temperatures.
• R 3 represents hydrogen, alkali metal cyanates and thiocyanates are used. Examples of leaving groups are halogen, methylthio or alkoxy, preferably methylthio.
• the introduction of the group: ##STR8## may also be effected indirectly by first reacting the amine (II) with a compound of the formula: ##STR9## in which P is a leaving group as defined above. This reaction may be effected in a solvent, e.g. ether or acetonitrile at a temperature from ambient to reflux. Treatment of the resulting compound of formula (III): ##STR10## where Y represents ⁇ NR 4 or ⁇ CH--NO 2 with a primary amine R 3 NH 2 at a temperature from ambient to reflux gives the desired end product.
• Y is a nitromethylene group ( ⁇ CHNO 2 ) or a cyanoimino group ( ⁇ N--CN) are prepared according to the following reaction scheme: ##STR11## wherein R 1 , R 2 , R 3 , n and X are as defined above.
• the amine starting material (II) is treated with 1,1-bis-methylthio-2-nitroethene in a suitable solvent, preferably acetonitrile or a lower alcohol, such as ethanol.
• a suitable solvent preferably acetonitrile or a lower alcohol, such as ethanol.
• the reaction may be carried out at about 20° C. to the reflux temperature of the reaction mixture.
• the reaction is substantially complete in about 8 hours to several days. It is preferred to stir the reaction mixture overnight at about 55°-60° C.
• the amine starting material (II) is reacted with dimethyl cyanodithioimidocarbonate in a suitable solvent, preferably acetonitrile or a lower alcohol, such as ethanol.
• a suitable solvent preferably acetonitrile or a lower alcohol, such as ethanol.
• the reaction may be carried out at about 20° C. to the reflux temperature of the reaction mixture.
• the reaction is substantially complete in about 1 hour to several days. It is preferred to stir the reaction mixture overnight at about room temperature.
• the next step of this reaction sequence is the same for Compounds IVA and IVB and involves the displacement of the methylthio group of Compound IVA and IVB by a loweralkylamino group.
• a loweralkyl amine is employed and the reaction is carried out by dissolving the amine in a solvent, such as a lower alcohol, preferably ethanol.
• the reaction is carried out at from 0° C. to the reflux temperature of the reaction mixture.
• the reaction mixture must either be maintained at from 0° C. to room temperature or, if heating is required, the reaction must be placed in a sealed reaction vessel. It is preferred to use atmospheric pressure for the reaction, and to keep the temperature at about room temperature or less.
• the reaction is complete in about 1 hour to several days, with most reactions requiring stirring overnight.
• the products (I-A and I-B) are isolated using techniques known to those skilled in this art.
• methylbenzofuran-2-carboxylic acid is esterified using ethanol in the presence of acid to prepare the ethyl ester derivative thereof.
• the preferred acid is a mineral acid such as sulfuric.
• the reaction is carried out generally at reflux for from 12 to 36 hours, using ethanol as the solvent.
• the methyl group is brominated with a brominating agent, preferably a free radical brominating agent such as N-bromosuccinimide in the presence of a free radical initiator such as ⁇ , ⁇ '-azobisisobutyronitrile used in catalytic amounts.
• a brominating agent preferably a free radical brominating agent such as N-bromosuccinimide
• a free radical initiator such as ⁇ , ⁇ '-azobisisobutyronitrile used in catalytic amounts.
• the reaction is carried out at from 35° C. to the reflux temperature of the reaction mixture and is generally complete in from 2 to 8 hours.
• An inert solvent, immune to bromination, such as carbon tetrachloride, is employed.
• the brominated compound is then treated with an amine to produce the aminomethyl side chain.
• the reaction is carried out in an inert solvent such as ether, tetrahydrofuran, and the like.
• the amine reagent is employed in excess, or a separate non-reactive base such as a tertiary amine, is employed to neutralize the liberated hydrogen bromide.
• the reaction is carried out at from 0° to 30° C. and is generally complete in from 0.5 to 3 hours.
• the 2-position ester is then reduced to the hydroxymethyl group using a reducing agent, such as lithium aluminum hydride, lithium borohydride and the like.
• a reducing agent such as lithium aluminum hydride, lithium borohydride and the like.
• the reaction is carried out in a solvent immune to reduction such as ether, tetrahydrofuran, and the like.
• the reaction is carried out at about 5° to 37° C. and generally is complete in from 1 to 3 hours.
• the 2-hydroxymethyl benzofuran is then treated with an amino alkyl mercaptan.
• the reaction is carried out in the presence of acid, generally mineral acid such as concentrated hydrochloric acid at from 5° to 30° C., and is complete in from 20 to 64 hours.
• acid generally mineral acid such as concentrated hydrochloric acid at from 5° to 30° C., and is complete in from 20 to 64 hours.
• the product is isolated using techniques known to those skilled in the art.
• an appropriately substituted benzofuran is lithiated and then treated with a compound Br(CH 2 ) m Br where m is as defined above.
• the reaction is carried out in an inert solvent such as ether, tetrahydrofuran and the like.
• the benzofuran is added to a solution of lithium diisopropylamide in the solvent in order to prepare the 2-lithium benzofuran intermediate which is then reacted with the dibromo compound.
• a reaction promoter such as hexamethylphosphoramide is usually present.
• the reaction is generally carried out at from -20° to 20° C., preferably at about 0° C. and is complete in about 3 to 10 hours.
• the bromo compound is then converted to the phthalimide with an alkali metal salt of phthalimide in a solvent such as dimethylformamide at from 20° to 60° C. preferably at room temperature, and is complete in about 12 to 30 hours.
• a solvent such as dimethylformamide
• the phthalimido derivative is then cleaved with hydrazine to prepare the amino group.
• the reaction is carried out at from 25° to 100° C. preferably from about 50° to 75° C., and is complete in about 2 to 24 hours.
• a solvent such a loweralkanol, preferably ethanol, is employed, and the product is isolated using techniques known to those skilled in the art.
• the starting group is the carboxylic acid which may esterified and then converted to the amide, or the amide may be prepared directly if the substituents on the remainder of the molecule would allow.
• the ester is prepared with ethanol in the presence of an acid as described in the esterification previously described.
• the amide is prepared with an appropriately substituted amine and a catalytic amount of a base such as an alkali metal alkoxide.
• a base such as an alkali metal alkoxide.
• the reaction is carried out in a solvent such as a lower alkanol at from 25° to 80° C. If temperatures higher than the boiling point of the reaction mixture are called for, a pressurized vessel may be employed.
• the reaction is generally complete in from 12 to 36 hours.
• the amide is then reduced to prepare the substituted amino methyl group.
• the reducing agent may be lithium aluminum hydride, borane, and the like and is carried out in a solvent such as ether, tetrahydrofuran, and the like and is generally complete in from 2 to 6 hours.
• the products are isolated using techniques known to those skilled in the art.
• N-Bromosuccinimide (37.4 g., 0.21 mole) is added to a solution of ethyl-6-methylbenzofuran-2-carboxylate (40.8 g., 0.2 mole) and ⁇ , ⁇ '-azobisisobutyronitrile (500 mg.) in carbon tetrachloride (300 ml.). The suspension is boiled under reflux for 3 hours. It is then cooled and the succinimide removed by filtration. The carbon tetrachloride solution is washed with water and dried over sodium sulfate. The solution is then evaporated at reduced pressure. The solid residue is recrystallized from hexane to yield 47.4 g.
• 6-(Dimethylaminomethyl)-2-benzofuranmethanol (28.3 g., 0.138 mole) is added to an ice-cold solution of cysteamine hydrochloride (17.2 g., 0.151 mole) in concentrated hydrochloric acid (70 ml.). The resulting solution is allowed to stand at room temperature for 45 hours. It is then cooled in an ice bath and made strongly basic by the addition of 10 N sodium hydroxide solution. The product is extracted with five portions of methylene chloride. The extracts are combined, washed with water and dried over Na 2 SO 4 . Evaporation of the solvent leaves 29.8 g.
• Step A Ethyl 7-methylbenzofuran-2-carboxylate, b.p. 164° C./18 mm. Hg.
• Step B Ethyl 7-bromomethyl)benzofuran-2-carboxylate, m.p. 81°-83° C.
• Step G --N-Cyano-N'-[2-(7-dimethylaminomethyl-2-benzofuranylmethylthio)ethyl]-N"-methylguanidine, m.p. 103.5°-105.5° C.
• n-Butyllithium solution (2.29 M in hexane, 44 ml., 0.1 mole) is added to a solution of diisopropylamine (10.1 g., 0.1 mole) in tetrahydrofuran (150 ml.) and hexamethylphosphoramide (15 ml.).
• the resulting solution is treated with benzofuran-6-carboxylic acid (8.1 g., 0.05 mole) and then with 1,4-dibromobutane (10.8 g., 0.05 mole) at 0° C.
• the mixture is stirred at 0° C. for 6 hours. It is then quenched with water, acidified with hydrochloric acid and extracted with ethyl acetate. Evaporation of the solvent gives 2-(4-bromobutyl)benzofuran-6-carboxylic acid.
• N,N-dimethyl-2-(4-aminobutyl)benzofuran-6-carboxamide 13.0 g., 0.05 mole
• lithium aluminum hydride (3.0 g., 0.08 mole) in tetrahydrofuran (60 ml.) at 25°-30° C.
• the mixture is stirred for 2 hours at 25°-30° C. and then is treated successively with 3 g. of water, 3 g. of 15% sodium hydroxide solution and 9 g. of water.
• the solid precipitate is removed by filtration.
• the tetrahydrofuran solution is evaporated at reduced pressure to provide 2-(4-aminobutyl)-6-dimethylaminomethyl)benzofuran.
• This compound is obtained by the reaction of 2-(4-aminobutyl)-6-(dimethylaminomethyl)benzofuran with dimethyl cyanodithioimidocarbonate following the procedure described in Example 1, Step F.
• This compound is obtained by the reaction of N-cyano-N'-[4-(6-dimethylaminomethyl-2-benzofuranyl)butyl]-S-methylisothiourea with methylamine following the procedure described in Example 1, Step G.
• N-cyano-N'-[2-(6-dimethylaminomethyl-2-benzofuranylmethylthio)ethyl]-N"-(2-propynyl)guanidine is obtained when the residual oil is chromatographed on silica gel with elution by an 8% solution of methanol in chloroform.
• This compound is prepared by the procedure described in Example 10 except that an equivalent quantity of benzylamine is substituted for the proparglyamine used in Example 10.

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• 1979
  • 1979-10-31 US US06/089,808 patent/US4238487A/en not_active Expired - Lifetime
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